A Multicenter Phase 2 Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, in Subjects with Relapsed or Relapsed and Refractory Multiple Myeloma
This is a Phase 2, open-label, nonrandomized, multi-cohort, multicenter Simon 2-stage study designed to assess the safety and efficacy of PCI-32765 in subjects with relapsed or relapsed and refractory MM.
Treatment of PCI-32765 420 mg once daily in the original protocol (hereafter referred to as Cohort 1) was designed to detect a meaningful signal of activity while minimizing risk of continuing enrollment under null conditions.
Amendment 1 was designed to further explore the optimal regimen by increasing doses of PCI-32765 and/or by routine combination with low dose dexamethasone.
Up to eighteen (18) subjects will be enrolled to each Cohort 2, 3, and
4, for a maximum total of 54 subjects.Stage 1 enrollment to Cohorts 3 and 4 may begin concurrently after
Cohort 2 Stage 1 enrollment is complete. If there is concurrent enrollment, Sponsor will implement centralized assignments into cohorts.
If >= 3 CBRs are observed within Cohorts 2, 3, or 4 in Stage 1, the Cohort(s) may be selected for expansion for up to a total of enrollment
The primary endpoint of the study is the CBR, defined as the proportion of subjects achieving sCR + CR + VGPR + PR + MR as assessed by investigator per modified IMWG criteria.
The secondary endpoints for this study are as follows:
* Safety parameters including the incidences and types of clinical adverse events, laboratory variables, and vital signs measurements.
* Duration of clinical benefit (DCB)
* Objective response rate (ORR=sCR + CR + VGPR + PR)
* Duration of objective response (DOR)
* Plasma PK of PCI-32765 and a major metabolite, PCI-45227
* Progression-free survival (PFS)
* Time to progression (TTP)
* Overall survival (OS)
* Hematologic improvement (HI)
1. Diagnosis of symptomatic MM (as defined by modified IMWG criteria, refer to Appendix 4 of the protocol) with measurable disease, defined here as having at least one of the following:
* Serum monoclonal (M protein) >= 0.5 g/dL as determined by serum
* protein electrophoresis (SPEP).
* Urine M-protein (UPEP) >= 200 mg/24 hrs.
* Serum free light chain (FLC) assay: involved FLC level >= 10 mg/dL (>= 100 mg/L) provided serum FLC ratio is abnormal.
2. Relapsed or relapsed and refractory MM after receiving at least 2 previous lines of therapy, 1 of which must be an immunomodulator (eg, Revlimid(RegisteredTM), thalidomide).
* Refractory myeloma (to most recent treatment) is defined as disease that is nonresponsive while on treatment or progressive disease within 60 days after the completion of the preceding treatment. Nonresponsive disease is defined as either failure to achieve minimal response or development of progressive disease while on therapy.
* Relapsed myeloma is defined as the occurrence of any of the following after most recent treatment:
o > 25% increase in M-protein from the lowest value obtained while on treatment (absolute increase must be >= 0.5g/dL by SPEP or >= 200 mg/24h by UPEP) or
o increase in the size and number of lytic bone lesions recognized on radiographs (compression fractures per se do not constitute a relapse).
3. Men and women >= 18 years of age.
4. Eastern Cooperative Oncology Group (ECOG) performance status <= 1.
5. Life expectancy of >= 12 weeks.
6. Ability to understand and willingness to sign a written informed consent form.
7. Ability to adhere with the study visit schedule and other protocol procedures.